Methods and compositions for applying pharmacologic agents to the ear

ABSTRACT

Methods and materials useful for applying pharmacologic agents to the ear are described. The methods involve delivering a composition that contains at least one viscogenic agent and at least one pharmacologic agent to the epidermal surface of the tympanic membrane via the ear canal. The composition is delivered to the tympanic membrane in a flowable form and, after delivery to the tympanic membrane, becomes sufficiently viscous such that the pharmacologic agent is localized against the tympanic membrane. Such compositions can be used to prophylactically and/or therapeutically treat middle and inner ear conditions, including otitis media.

TECHNICAL FIELD

The invention relates to methods and materials for applyingpharmacologic agents to the ear. More particularly, the inventionfeatures methods and materials for applying pharmacologic agents to theexternal, epidermal surface of a tympanic membrane for treatingdisorders of the ear.

BACKGROUND

Otitis media (OM) is very common, especially in children. OM oftenbegins with a viral infection of the upper respiratory tract that altersthe micro-environment of the upper respiratory tract, Eustachian tube,and middle ear such that bacteria resident in the nasopharynx invade andpopulate the middle ear. This invasion can inflame and block theEustachian tube, interfering with middle ear ventilation, pressureequilibration, and drainage. Fluids accumulate and pressure increases inthe normally air-filled middle ear space, causing great pain. In severecases of OM, sound perception structures can be damaged. Persistent orrecurrent OM may be caused by bacteria that emerge from dormancy in themiddle ear, having been shielded from antibiotics by a slimy biofilm.

OM currently is treated using antibiotics and/or by inserting atympanostomy tube through a surgical incision in the tympanic membraneso as to drain and depressurize the middle ear space. The efficacy ofantibiotic treatment is limited by the route of delivery. Antibioticscan be delivered systemically, but a high dose often is required toattain therapeutic levels (i.e., above minimum inhibitory concentration)in the middle ear, and such levels often are attained after asignificant lag time. Antibiotics also can be delivered by lavage, orvia drops into the ear canal. Such delivery routes can be difficult tocontrol, and often are not effective to achieve prolonged therapeuticlevels of antibiotic in the middle ear. Antibiotics also can bedelivered by injection into the middle ear, or by insertingantibiotic-impregnated materials into the middle ear, but such methodsinvolve piercing or cutting the tympanic membrane, which requiresgeneral anesthesia and can damage the tympanic membrane. Surgicalinsertion of tympanostomy tubes also carries risks, includingtympanoclerosis (i.e., scarring of the tympanic membrane), hearing loss,persistent otorrhea (i.e., discharge of pus from the tube) andinfection.

The National Institute on Deafness and Other Communication Disorders(NIDCD), a part of the National Institutes of Health, recently launcheda $2,000,000 funding initiative to support the development ofalternative strategies and new approaches for preventing and treatingOM. In its request for applications (RFA-DC-02-002), NIDCD stated that:(1) OM causes significant childhood morbidity and is increasinglyaffecting general public health; (2) OM is the leading reason forEmergency Room visits; (3) OM is the second leading reason for doctors'office visits; (4) OM is the leading reason of childhood antibioticsprescriptions, accounting for more than 40% of all outpatient antibioticprescriptions; (5) OM is the leading reason for childhood hearing loss;and (6) OM is the leading reason for general anesthesia in children. Inaddition, NIDCD blamed the use of broad-spectrum antibiotics to treat OMfor the alarming emergence of multiple antibiotic resistant bacteria inthree of the genera that can cause OM (Streptococcus pneumoniae,non-typeable Haemophilus influenzae, and Moraxella catarrhalis). As aconsequence, many first and second line antibiotics are becoming lessand less effective against OM and other diseases, including pneumoniaand meningitis. NIDCD concluded that “the development of novelapproaches for the study, treatment and prevention of OM is urgentlyneeded to: 1) reduce OM morbidity and the associated costs; and 2)preserve the efficacy of antibiotics used for the treatment of OM andother common serious diseases.”

SUMMARY

The invention is based, in part, on the discovery that compositionscontaining one or more pharmacologic agents can be formulated such thatthat they can be delivered to the external, epidermal surface of thetympanic membrane in a liquid-like form, then, upon delivery, transformto a solid-like state such that the composition remains localizedagainst the tympanic membrane. Delivery of such compositions to thetympanic membrane can provide more effective ways to treat middle andinner ear disorders (e.g., OM).

In one aspect, the invention features a method for administering apharmacologic agent to a mammal (e.g., a rodent or a human). The methodincludes applying a formulation to the epidermal surface of a tympanicmembrane of the mammal, wherein the formulation includes a viscogenicagent and at least one pharmacologic agent, wherein the formulation hasa viscosity less than 100,000 cps, and wherein the formulation, afterapplication to the tympanic membrane, has a yield stress sufficient tomaintain the formulation against the tympanic membrane. The viscogenicagent can be gellan, N-isopropyl acrylamide with sodium acrylate andn-N-alkylacrylamide, polyacrylic acid with polyethylene glycol,polymethacrylic acid with polyethylene glycol, CARBOPOL® withhydroxypropylmethylcellulose, cellulose acetate hydrogen phthalatelatex, sodium alginate, or a reverse thermosetting gel such as apoloxamer or a poloxamine. The pharmacologic agent can be an antibiotic,an anti-fungal, or an anti-viral agent. The pharmacologic agent cantransfer across the tympanic membrane into the middle ear space. Theantibiotic can be a penicillin, e.g., amoxicillin oramoxicillin-clavulanate. The antibiotic can be a sulfa-basedcombination, e.g., erythromycin-sulflsoxazole ortrimethoprim-sulfamethoxazole. The antibiotic can be a macrolide/azide,e.g., azithromycin or clarithromycin. The antibiotic can be acephalosporin, e.g., cefaclor, cefprozil, cefuroxime axetil, loracarbef,cefdinir, cefixime, cefpodoxime proxetil, ceftibuten, or ceftriaxone.The at least one pharmacologic agent can include an antibiotic and ananti-inflammatory agent, and further can include an anesthetic. Theformulation further can include an adhesion facilitator, a permeabilityenhancer, a bioadhesive, a hygroscopic agent, an ear war softener, or apreservative.

In another aspect, the invention features a kit that includes aformulation and instructions indicating that the formulation is to beapplied to a tympanic membrane, wherein the formulation includes aviscogenic agent and at least one pharmacologic agent, wherein theformulation has a viscosity less than 100,000 cps, and wherein theformulation has a yield stress sufficient, after application to thetympanic membrane, to maintain the formulation against the tympanicmembrane.

The invention also features a rodent (e.g., a chinchilla) that includesa formulation applied to the epidermal surface of its tympanic membrane,wherein the formulation includes a viscogenic agent and at least onepharmacologic agent, wherein the formulation has a viscosity less than100,000 cps, and wherein the formulation has a yield stress sufficientto be maintained against the tympanic membrane.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used to practicethe invention, suitable methods and materials are described below. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a graph of free (unbound) amoxicillin concentration inchinchilla middle ear fluid as a function of time after drug dosing viathe external ear canal; mean data and standard error bars (n=3 to 5 ateach time point).

FIG. 2 is a graph of clarithromycin concentration in chinchilla middleear fluid as a function of time after drug dosing via the external earcanal; mean data and standard error bars (n=12 to 23 at each timepoint).

DETAILED DESCRIPTION

In general, the invention provides methods for applying pharmacologicagents to the ear using compositions containing one or morepharmacologic agents and one or more viscogenic agents. Compositions arespecifically formulated such that they can be delivered to the external,epidermal surface of the tympanic membrane in a liquid-like state, i.e.,a flowable form. After administration, however, the compositiontransforms into a solid-like state such that the composition remains incontact with the tympanic membrane. As a result, the composition remainslocalized against the tympanic membrane and the pharmacologic agent cantransfer across the tympanic membrane into, for example, the middle earspace, providing a more effective way to treat middle and inner eardisorders (e.g., OM). Suitable compositions also can contain otherconstituents, e.g., to facilitate the adhesion of the formulation to thetympanic membrane and/or to increase the permeability of the tympanicmembrane to a pharmacologic agent.

Compositions of the invention have a viscosity of less than 100,000centipoise (cps) at 25° C. Viscosity refers to the composition'sresistance to flow. Compositions having a volume of 0.5 mL that can passthrough a 19-gauge needle attached to a 1-mL tuberculin syringe in lessthan 1 minute at 25° C., by reasonable force and without aid ofmechanical devices, typically have a viscosity of less than 100,000 cps.Viscosity of a composition can be determined using a viscometer (e.g.,from Brookfield) calibrated with commercially available viscositystandards.

Compositions of the invention also have a minimum yield stress that issufficient for maintaining the formulation against the tympanicmembrane. Yield stress refers to the amount of force that, when appliedto a solid material, causes the solid material to exhibit liquid-likebehavior in that it continues to deform with no further increase instress. Minimum yield stress of compositions of the invention isdependent on the thickness of the applied gel, but is independent of thegeometry of the gel and the temperature of the environment. As usedherein, minimum yield stress of the composition is in reference to anapplied gel that has a thickness of 4 mm and a density of 1 g/L. Yieldstress (σ₀) is represented as σ₀=ρgh, where ρ is the density, g is theacceleration due to gravity, and h is the layer thickness. Typically,minimum yield stress is about 39 pascals (Pa). Methods described hereinalso can be used to estimate if a composition has sufficient yieldstress to be maintained against the tympanic membrane. For example, atest composition can be administered to the ear of an animal such as achinchilla and the ear of the animal can be monitored to determine ifthe composition transforms to a more solid-like state and is maintainedagainst the tympanic membrane. See Example 1.

Viscogenic Agents

As used herein, viscogenic agent refers to a polymer or other chemicalmoiety that increases the viscosity of a fluid. Suitable viscogenicagents, when included in a composition of the invention, allow thecomposition to transform from a liquid-like state (e.g., flowable) at25° C. to a solid-like state (e.g., a gel) after contact with thetympanic membrane, and can be non-biodegradable, i.e., not broken downby chemicals or enzymes naturally present in a mammal, or biodegradable.Compositions include an amount of viscogenic agent effective to yield aviscosity of the composition of less than 100,000 cps at 25° C. (e.g.,less than 90,000, 60,000, 30,000, 20,000, or 10,000 cps) and, generally,a minimum yield stress of 39 Pa after application to the tympanicmembrane. Typically, a composition includes 0.05 to 50% of a viscogenicagent (e.g., 0.15 to 25, 5 to 45, 10 to 40, 12 to 37, 15 to 35, 17 to33, or 20 to 30% of a viscogenic agent).

Exemplary viscogenic agents include gellan (GELRITE® or KELCOGEN ®),CARBOPOL® 940 with hydroxypropylmethylcellulose (HPMC), N-ispropylacrylamide (NiPAAm) with sodium acrylate and n-N-alkylacrylamide,polyacrylic acid with polyethylene glycol (PEG) or polymethacrylic acidwith PEG, cellulose acetate hydrogen phthalate latex (CAP), sodiumalginate, and nonionic surfactants such as poloxamers (PLURONIC®) andpolyoxamine (TETRONIC®) reversible temperature-dependent gellingsystems. Gellan is a natural polymer, anionic deacetylated exocellularpolysaccharide, secreted by Pseudomonas elodea. The tetrasacchariderepeating unit consists of one α-L-rhamnose, one β-D-glucuronic acid,and two β-D-glucose moieties. The in situ gelling mechanism of gellan iscation-induced (e.g., presence of calcium ions) andtemperature-dependent (e.g., physiologic temperature). Gelation isthermally reversible. CARBOPOL ® 940 with HPMC gels in situ in apH-dependent manner. CARBOPOL® is the gelling agent and the HPMC is usedto enhance the viscosity of the gel. NiPAAm with sodium acrylate andn-N-alkylacrylamide is a terpolymer hydrogel that can undergo atemperature based reversible sol-gel transformation. Sodium acrylate andn-N-alkylacrylamide are used to modify the properties of the hydrogel,and in particular, the transition temperature. Polyacrylic acid with PEGor polymethacrylic acid with PEG is thought to gel based on hydrogenbonding. Polyacrylic acid can be dissolved in hydroalcoholic solutionand after being injected, the alcohol diffuses out causing the polymersto precipitate and gelling of the solution. CAP is a nanoparticulatesystem that gels in a pH-dependent manner. The active compound(pharmacologic agent) is adsorbed partially onto the surface of thepolymer particles. Sodium alginate gels in the presence of calcium orother polyvalent ion.

Nonionic Surfactants such as poloxamers and poloxamines are particularlyuseful. Poloxamers are well known in the pharmaceutical arts and aredescribed, for example, by Irving R. Schmolka in Poloxamers in thePharmaceutical Industry, in Polymers for Controlled Drug Delivery,Chapter 10 (Peter J. Tarcha ed., 1990). Poloxamers are triblockcopolymers because they are composed of two different polymer blocks(i.e., hydrophilic poly(oxyethylene) blocks and hydrophobicpoly(oxypropylene) blocks) configured as a triblock ofpoly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene). Poloxamers areone class of block copolymer surfactants having a propylene oxide blockhydrophobe and an ethylene oxide hydrophile. Poloxamers are commerciallyavailable (e.g., Pluronic® polyols are available from BASF Corporation).Alternatively, polaxamers can be synthesized by known techniques.

Poloxamers previously have been thought to lack utility foradministering pharmacologic agents, given their non-biodegradability,their water solubility and their relatively rapid drug release kinetics(see e.g., U.S. Pat. No. 6,201,072). Nonetheless, as described herein,poloxamers share a property that is advantageous for applyingformulations to the tympanic membrane: aqueous formulations ofpoloxamers exhibit reverse thermal gelation, or reverse thermosetting.When an aqueous poloxamer formulation is heated over its gelationtemperature, its viscosity increases and it transforms into a gel. Whenan aqueous poloxamer formulation is cooled below its gelationtemperature, its viscosity decreases and it transforms into a liquid.The transition between gel and liquid does not involve a change in thechemical composition of the formulation, and is reversible andrepeatable. The gel-liquid transition temperature of an aqueouspoloxamer formulation can be adjusted by one of ordinary skill in theart using routine experimentation (e.g., by manipulating poloxamerconcentration, pH and presence of other ingredients in the formulation).In some embodiments, compositions have a gelation temperature that isgreater than the ambient temperature and less than or equal to thetemperature of the tympanic membrane. Such compositions can beconveniently applied via an individual's ear canal as a liquid and thencan transform into a gel against the tympanic membrane, therebymaintaining the drug in the formulation in close proximity to thetympanic membrane.

Pharmacologic Agents

A composition of the invention also contains at least one pharmacologicagent (i.e., a chemical or biological molecule that has a desired effectwhen applied in an effective amount to the tympanic membrane). Theamount of pharmacologic agent present in the composition is dependent onthe type of pharmacologic agent and its known effective dosage.Typically, pharmacological agents are present in amounts ranging from0.1% to 50% (e.g., 0.25% to 15%). A composition can include any type ofpharmacologic agent, including, e.g., an adrenocorticoid(corticosteroid, steroid), analgesic, analgesic adjunct,analgesic-anesthetic, anesthetic, antibiotic, antibacterial,anti-infective, antibiotic therapy adjunct, antidote, anti-emetic,anti-fungal, antiinflammatory, anti-vertigo, anti-viral, biologicalresponse modifier, cytotoxic, diagnostic aid, immunizing agent,immunomodulator, proteins, peptides, and other agents that may useful intreating ear disorders. Analgesic, analgesic adjunct,analgesic-anesthetic, anesthetic, antibiotic, antibacterial,anti-infective, antibiotic therapy adjunct, anti-fungal,anti-inflammatory, anti-viral, and peptides are particularly useful. Acomposition of the invention can include a plurality of pharmacologicagents, including two or more agents within the same class (e.g., twodifferent antibiotics) or two or more agents of various types, dependingon the effect desired. For example, to fight a bacterial infection, toreduce tissue inflammation, and to alleviate irritation, a compositioncan contain an antibacterial, an anti-inflammatory, and an anesthetic oranalgesic. Those skilled in the art can identify pharmacologic agentsand combine them as needed to achieve a desired effect.

Exemplary adrenocorticoids include betamethasone, cortisone,dexamethasone, hydrocortisone, methylprednisolone, paramethasone,prednisolone, prednisone, and triamcinolone. Exemplary analgesicsinclude acetaminophen, aspirin, buprenorphine, butalbital, butorphanol,codeine, dezocine, diflunisal, dihydrocodeine, etodolac, fenoprefen,fentanyl, floctafenine, hydrocodone, hydromorphone, ibuprofen,ketoprofen, ketorolac, levorphanol, magnesium salicylate, meclofenamate,mefenamic acid, meperidine, meprobamate, methadone, methotrimeprazine,morphine, nalbuphine, naproxen, opium, oxycodone, oxymorphone,pentazocine, phenobarbital, propoxyphene, salsalate, and sodiumsalicylate. One exemplary analgesic adjunct is caffeine. Exemplaryanesthetics include articane-epinephrine, bupivacaine, chloroprocaine,etidocaine, ketamine, lidocaine, mepivacaine, methohexital, prilocaine,propofol, propoxycaine, tetracaine, and thiopental. One exemplaryanalgesic-anesthetic is antipyrine-benzocaine.

Exemplary antibiotics, anti-bacterials, and anti-infectives includesulfonamides (e.g., sulfanilamide, sulfadiazine, sulfamethoxazole,sulfisoxazole, para-aminobenzoic acid, or sulfacetamide),trimethoprim-sulfamethoxazole, quinolones (e.g., ciprofloxacin,ofloxacin, or nalidixic acid), β-lactam antibiotics such as penicillinsor cephalosporins, aminoglycosides (e.g., kanamycin, tobromycin,gentamycin C, amikacin, neomycin, netilmicin, streptomycin, orvancomycin), tetracyclines, chloramphenicol, and macrolides (e.g.,erythromycin, clarithromycin, or azithromycin). Non-limiting examples ofsuitable penicillins include penicillin G, penicillin V, methicillin,oxacillin, nafeillin, ampicillin, and amoxicillin. Non-limiting examplesof suitable cephalosporins include cephalothin, cefdinir, cefozolin,cephalexin, cefadraxal, cefamandole, cefoxitin, cefaclor, cefonicid,cefoletan, cefotaxime, ceftizoxime, cefrtriaxone, cefditoren, andcefepine. Exemplary antibiotics useful for treating OM includepenicillins such as amoxicillin and amoxicillin-clavulanate(Augmentin®); sulfa-based combinations such aserythromycin-sulfisoxazole (Pediazole), trimethoprim-sulfamethoxazole(Bactrim, Septra®); macrolides/azalides such as azithromycin(Zithromax®) or clarithromycin (Biaxin®); second-generationcephalosporins such as cefaclor (Ceclor®), cefprozil (Cefzil®),cefuroxime axetil (Ceftin®), or loracarbef (Lorabid®); and thirdgeneration cephalosporins such as cefdinir (Omnicef®), cefixime(Suprax®), cefpodoxime proxetil (Vantin®), ceftibuten (Cedax®),cefditoren (Spectracef,®), and ceftriaxone (Rocephin®).

Suitable anti-emetics include buclizine, chlorpromazine, cyclizine,dimenhydrinate, diphenhydramine, diphenidol, domperidone, dronabinol,haloperidol, hydroxyzine, meclizine, metoclopramine, nabilone,ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine,thiethylperazine, triflupromazine, and trimethobenzamine. Exemplaryantifungals include amphotericin B, clioquinol, clotrimazole,fluconazole, flucytosine, griseofulvin, ketoconazole, miconazole, andpotassium iodide. Exemplary anti-inflammatory agents include aluminumacetate, aspirin, betamethasone, bufexamac, celecoxib, dexamethasone,diclofenac, etodolac, flurbiprofen, hydrocortisone, indomethacin,magnesium salicylate, naproxen, prednisolone, rofecoxib, salsalate,sulindac, and triamcinolone. Exemplary anti-vertigo agents suitable forthe invention include belladonna, dimenhydrinate, diphenhydramine,diphenidol, meclizine, promethazine, and scopolamine. Exemplaryanti-viral agents suitable for the invention include acyclovir,amantadine, delavirdine, didanosine, efavirenz, foscamet, ganciclovir,indinavir, nelfinavir, ribavirin, ritonavir, zalcitabine, andzidovudine. Exemplary biological response modifiers include aldesleukin,interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3,interferon γ, and levamisole. Exemplary cytotoxic agents includepodofilox and podophyllum. Exemplary immunizing agents include influenzavirus vaccine, pneumococcal vaccine polyvalent, and immune globulin. Anexemplary immunomodulator invention is interferon γ. Other pharmacologicagents suitable for the invention include betahistine (e.g., fortreating the nausea, dizziness, and ringing in the ears that occur inMénière's disease), prochlorperazine, and hyoscine.

Other Constituents of Compositions of the Invention

In some embodiments, compositions of the invention include one or morecompounds in addition to the viscogenic and pharmacologic agents. Forexample, a composition can include one or more of the followingcompounds: a solvent or diluent such as saline, a bioadhesive, apermeability enhancer, a hygroscopic agent, an earwax softener,preservative (e.g., an antioxidant), or other additives. Such compoundscan be present in the composition in amounts ranging from 0.01% to 99%(e.g., 0.01 to 1, 0.01 to 10, 0.01 to 40, 0.01 to 60, 0.01 to 80, 0.5 to10, 0.5 to 40, 0.5 to 60, 0.5 to 80, 1 to 10, 1 to 40, 1 to 60, 1 to 80,5 to 10, 5 to 40, 5 to 60, 5 to 80, 10 to 20, 10 to 40, 10 to 60, 10 to80, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, or 70 to 80%). Forexample, a composition can include one or more viscogenic agents (e.g.,PLURONIC® F-127 and CARBOPOL®), one or more pharmacologic agents, andone or more permeability enhancers (e.g., vitamin E). In otherembodiments, a composition can include one or more viscogenic agents,one or more pharmacologic agents, and one or more earwax softeners.Compositions also can include one or more viscogenic agents, one or morepharmacologic agents, one or more hygroscopic agents, and one or morepreservatives. It is noted that certain agents can fulfill differentroles within the formulation. For example, CARBOPOL® corbopol canfunction as a viscogenic agent or as a bioadhesive, depending on itsconcentration. Vitamin E can function as a permeability enhancer, apreservative, and an antioxidant.

A bioadhesive facilitates the adhesion of the composition to thetympanic membrane. Suitable bioadhesives include hydrocolloids such as:acacia; agar agar; alginates (e.g., alginic acid and sodium alginate);CARBOPOL®; carboxymethylcellulose sodium; carboxymethylcellulosecalcium; dextran; gelatin; guar gum; heparin; hyaluronic acid;hydroxyethylcellulose; karaya gum; methylcellulose; pectin; polyacrylicacid; polyethylene glycol; poly-N-vinyl-2-pyrrolidone; and tragacanth.

Permeability enhancers increase the permeability of the tympanicmembrane to a pharmacologic agent. Exemplary permeability enhancersinclude: alcohols (e.g., ethanol and isopropanol); polyols (e.g.,n-alkanols, limonene, terpenes, dioxolane, propylene glycol, ethyleneglycol, and glycerol); sulfoxides (e.g., dimethylsulfoxide,dimethylformamide, methyl dodecyl sulfoxide, and dimethylacetamide);esters (e.g., isopropyl myristate/palmitate, ethyl acetate, butylacetate, methyl proprionate, and capric/caprylic triglycerides);ketones; amides (e.g., acetamides); oleates (e.g., triolein);surfactants (e.g., sodium lauryl sulfate); alkanoic acids (e.g.,caprylic acid); lactams (e.g., azone); alkanols (e.g., oleyl alcohol);dialkylamino acetates; polyunsaturated fatty acids (e.g., linoleic,alpha-linolenic, and arachidonic); oleic acid; cod-liver-oil; mentholderivatives (e.g., 1-menthol); Squalene; glycerol monoethers derivedfrom linear saturated fatty alcohols; flavones (e.g., chamomileapigenin, luteolin, and apigenin 7-ο-β-glucoside); vitamin E(α-tocopherol) and esters and analogs thereof; and Senkyu (LigusticiChuanxiong Rhizome) ether extract.

Hygroscopic agents such as fructose, phthalic acid, and sorbitol,facilitate the transfer of fluid from the middle ear across the tympanicmembrane into the gel matrix. Hygroscopic agents can help alleviate painassociated with fluid accumulation and pressurization of the middle ear,and can concentrate a pharmacologic agent in smaller fluid volume in themiddle ear.

Earwax softeners (e.g., docusate, olive oil, sodium bicarbonate, urea,or hydrogen peroxide) facilitate contact between the tympanic membraneand the composition. An antioxidant such as ascorbic acid and benzoicacid or other preservatives can be used to extend the shelf life of theformulation during storage.

Methods of Applying a Composition to the Tympanic Membrane

A composition of the invention can be applied to the epidermal surfaceof a tympanic membrane via the external auditory canal to, for example,treat a middle or inner ear disorder (e.g., OM). Compositions of theinvention also can be applied prophylactically (e.g., to prevent thedevelopment of a middle or inner ear disorder). A composition can betargeted to any part of the tympanic membrane, including the pars tensa,the lower part of the tympanic membrane, or pars flaccida, the upperpart of the tympanic membrane. In adult humans, the tympanic membrane isabout nine to ten mm in diameter and has a thickness ranging from 30 to230 μm (about 100 μm on average). The pars flaccida makes up less than3% of the tympanic membrane area in humans and animals such as cats,guinea pigs, and chinchillas. In other mammals (e.g., gerbils, rabbits,rats, and mice), the pars flaccida makes up 10% to 25% of the tympanicmembrane area. A thin epidermal layer (approximately 15 to 30 μm thick)covers the human tympanic membrane, while a thick epidermal layer(approximately 75 to 150 μm thick) covers other areas of the human body.Five to ten layers of cells cover the pars flaccida, while three to fivelayers of cells cover the pars tensa. Thus, the pars tensa often isthinner than other parts of the tympanic membrane and may be morepermeable to a pharmacologic agent. The central portion of the parstensa provides the active vibrating area in response to sound.

Any method known in the art can be used to apply a composition of theinvention to the tympanic membrane. For example, a composition can beapplied to the tympanic membrane using a fluid dispensing device. Adispensing device typically has a reservoir coupled to a conducting tubethat directly or indirectly receives a flowable composition from thereservoir and conducts the composition to a dispensation outlet. One ofordinary skill can make a simple dispensing device as a matter ofroutine from a syringe connected to flexible tubing. A dispensing devicealso can be made by replacing the needle of a tympanocentesis devicesuch as the CDT® Speculum (Walls Precision Instruments LLC, Casper,Wyo., USA) with a fluid conducting tube. A dispensing device can beattached to a pneumatic or diagnostic otoscope head (e.g., from WelchAllyn®, Skaneateles Falls, N.Y., USA) to create a precise platform forapplying a composition to the tympanic membrane.

Depending on the composition and the middle or inner ear disorder, itmay be desirable to remove the composition from the ear. This can beaccomplished manually using a cotton swab or forceps. A syringe or bulbalso can be used to inject water, saline or other biocompatible aqueoussolutions to soften, dissolve and/or flush out the formulation. In otherembodiments, compositions simply may slough off the tympanic membraneafter a period of time and fall out of the ear (e.g., during exercise orbathing). Biodegradable formulations may not need to be removed from theear.

Articles of Manufacture

Compositions described herein can be combined with packaging materialand sold as articles of manufacture or kits. Components and methods forproducing articles of manufactures are well known. The articles ofmanufacture may combine one or more compositions described herein. Inaddition, the articles of manufacture may further include one or more ofthe following: sterile water or saline, pharmaceutical carriers,buffers, or fluid-dispensing devices. A label or instructions describinghow the composition can be delivered to the ear for treatment of inneror middle ear disorders may be included in such kits. The compositionsmay be provided in a pre-packaged form in quantities sufficient forsingle or multiple administrations.

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

EXAMPLES Example 1

Trans-Tympanic Membrane Delivery of Amoxicillin

Flowable formulations containing 20% Pluronic® PF-127 (Sigma productnumber P-2443, Lot number 99H1194) and a targeted drug load ranging from0.3 mg to 5.2 mg of amoxicillin (Sigma product number A-8523, Lot number29F0730) were prepared for administration to the tympanic membrane ofadult chinchillas via the outer ear canal. See Table 1 (first five rows)for the composition of each formulation. Each formulation was dispensedusing a 1-ml tuberculin syringe fixed to a blunted needle. With theanimal's head tilted on one side and using an otoscope, the syringe wasinserted into the ear canal approaching the tympanic membrane and theformulation (300 to 350 μl) was slowly dispensed. The chinchilla wasmaintained recumbent for about one minute, or until the formulationturned opaque, indicating that the formulation had gelled.

Blank phosphate buffer solution (PBS) was instilled into the middle earof the chinchilla. Amoxicillin concentration in the middle ear fluid wasdetermined by direct microdialysis sampling of the lower bullae andHPLC-UV analysis for 20 hours while the chinchilla was awake. Meanunbound (pharmacologically active) amoxicillin levels (n=3 to 5 at eachtime point, mean and standard error) in the middle ear fluid increasedto approximately 75 μg/ml after 5 hours. See FIG. 1.

TABLE 1 Final Pluronic ETOH PEG 4000 Tween20 Tween80 IPM TransitionTransition F-127 Solvent (v/v) (w/v) (w/v) (w/v) (v/v) CARBOPOL Temp(°C.) Drugs(s) Temp(° C.) 20% PBS — — — — — 0.2%* 20% PBS — — — — — 0.02%*20% PBS — — — — — 0.1%* 20% Saline 2% 2% — — — 1.5%* 20% Saline 2% 2% —— 3.0% 1.5%* 20% PBS 3% 0.20% 0.25%*** *drug is amoxicillin; ***drug isclarithromycin

Example 2

Trans-Tympanic Membrane Delivery of Clarithromycin

Flowable formulations containing 20% Pluronic® PF-127 (Sigma productnumber P-2443, Lot number 99H1194) and 0.25% (w/v) clarithromycin (USPstandard 13437, Lot number F-2) (see last row of Table 1) wereadministered to the tympanic membranes of adult chinchillas. Theformulations had a solution to gel transition temperature of about 28°C. The formulations were administered via the outer ear canal using a1-ml tuberculin syringe attached to a rounded oral gavage tube. With theanimal's head tilted on one side and using an otoscope, the syringe wasinserted into the ear canal approaching the tympanic membrane and theformulation (0.2 to 0.5 mL; clarithromycin dosage=0.5 to 1.25 mg perear) was slowly dispensed. The chinchilla was maintained recumbent forabout ten minutes to allow the formulation to gel. The solutionsgenerally transitioned to a gel state sufficient to maintain theformulation against the tympanic membrane transition within one to twominutes after administration, as determined by otoscopy.

Blank phosphate buffer solution (PBS) was instilled into the middle earof the chinchilla. Clarithromycin concentration in the middle ear fluidwas determined by direct sampling from bullae and LC-MS-MS analysis. SeeFIG. 2, which plots clarithromycin concentration as a function of timepost-administration for 12–23 dosed ears.

Example 3

Viscosity and Yield Stress

The viscosity of the commercially available poloxamer 407 20% gel(Gallipot® Polox Gel 20%, preserved and buffered pH 5.0) was measured at13.5° C. Since the transition temperature of this product is about 14.5°C., viscosity could not be measured at 25° C. The viscosity at 13.5° C.was about 350–400 cps.

Yield stress of the same product was measured at temperatures rangingfrom 23 to 27.5° C. after it had gelled. The measured yield stressranged from 80 to 400 Pa, significantly higher than the minimum yieldstress of 39.2 Pa required to maintain the composition against thetympanic membrane.

Example 4

Flowable Formulations

Flowable formulations containing 20% Pluronic® PF-127 (Sigma productnumber P-2443, Lot number 99H1194) and one or more pharmacologic agents(e.g., 0.5to 1.5% (w/v)) can be prepared containing the componentsdescribed in Table 2.

TABLE 2 Final Pluronic ETOH PEG 4000 Tween20 Tween80 IPM TransitionTransition F-127 Solvent (v/v) (w/v) (w/v) (w/v) (v/v) Temp(° C.) Temp(°C.) 20% PBS 3% — 5.0% — — 20% PBS 3% 2% — — — 28 20% PBS 3% — 5.0% — —28 <33.7 20% PBS 3% — — 4.6% — 28 31 20% PBS 3% 2% — — 5.0% 27 <31 20%PBS 3% — — 4.8% — 20% PBS — — — 0.6% — 20% PBS — 2% — — 5.0% 20% PBS —2% — — — 20% PBS — 2% — — 1.0% 20% PBS — 2% — — 2.5%

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A method for administering a pharmacologic agent to the middle ear ofa mammal, said method comprising applying a formulation to the epidermalsurface of a tympanic membrane of said mammal, wherein said formulationis aqueous and comprises a viscogenic agent and at least onepharmacologic agent, wherein said formulation is flowable and has aviscosity less than 100,000 cps, and wherein said formulation, afterapplication to said tympanic membrane, forms a gel that has a yieldstress sufficient to maintain said formulation against said tympanicmembrane, wherein said pharmacologic agent transfers across saidtympanic membrane into the middle ear space.
 2. The method of claim 1,wherein said viscogenic agent is gellan.
 3. The method of claim 1,wherein said viscogenic agent is N-isopropyl acrylaniide with sodiumacrylate and n-N-allcylacrylamide.
 4. The method of claim 1, whereinsaid viscogenic agent is polyacrylic acid with polyethylene glycoL. 5.The method of claim 1, wherein said viscogenic agent is polymethacrylicacid with polyethylene glycol.
 6. The method of claim 1, wherein saidviscogenic agent is poly acrylic acid withhydroxypropylinethylcellulose.
 7. The method of claim 1, wherein saidviseogenic agent is cellulose acetate hydrogen phthalate latex.
 8. Themethod of claim 1, wherein said viscogenic agent is sodium alginate. 9.The method of claim 1, wherein said viscogenic agent is a reversethermosetting gel.
 10. The method of claim 9, wherein said viscogenicagent is a poloxamer.
 11. The method of claim 9, wherein said viscogenicagent is a poloxamine.
 12. The method of claim 1, wherein saidpharmacologic agent is an antibiotic, an anti-fungal, or an anti-viralagent.
 13. The method of claim 12, wherein said antibiotic is apenicillin.
 14. The method of claim 13, wherein said penicillin isselected from the group consisting of amoxicillin andamoxicillin-clavulanate.
 15. The method of claim 12, wherein saidantibiotic is a sulfa-based combination.
 16. The method of claim 15,wherein said sulfa-based combination is selected from the groupconsisting of: erythromycin-sulfisoxazole andtriniethoprim-sulfametboxazole.
 17. The method of claim 12, wherein saidantibiotic is a macrolide/azide.
 18. The method of claim 17, whereinsaid macrolide/azide is selected from the group consisting ofazithromycin and clarithromycin.
 19. The method of claim 12, whereinsaid antibiotic is a cephalosporin.
 20. The method of claim 19, whereinsaid cephalosporin is selected from the group consisting of: cefaclor,cefprozil, cefuroxime axetil, loracarbef, cefdinir, cefixime,cefpodoxlime proxetil, ceftibuten, and ceftriaxone.
 21. The method ofclaim 1, wherein said at least one pharmacologic agent comprises anantibiotic and an anti-inflammatory agent.
 22. The method of claim 21,wherein said at least one pharmacologic agent further comprises ananesthetic.
 23. The method of claim 1, wherein said formulation furthercomprises an adhesion facilitator, a permeability enhancer, abioadhesive, a hygroscopic agent, an ear wax softener, or apreservative.
 24. the method of claim 1, wherein said mammal is a human.25. The method of claim 1, wherein said mammal is a rodent.